Pain Pathways

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An Introduction to Pain Pathways and Pain “Targets”
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From Vaskar Das, An Introduction to Pain Pathways and Pain “Targets”. In: Theodore J. Price and
Gregory Dussor, editors, Progress in Molecular Biology and Translational Science, Vol. 131, Burlington:
Academic Press, 2015, pp. 1-30.
ISBN: 978-0-12-801389-2
© Copyright 2015 Elsevier Inc.
Academic Press
Author's personal copy
CHAPTER ONE
An Introduction to Pain Pathways

and Pain “Targets”
Vaskar Das1
Behavioral
1
and Brain Sciences, The University of Texas at Dallas, Richardson, Texas, USA
Corresponding author: e-mail address: vxd150530@utdallas.edu
Contents
1. An Introduction to Pain and Pain Pathways 2
1.1 Neuropathic pain 5
1.2 Inflammatory Pain 7
2. Ion Channels, Receptors, and Other “Targets” for Persistent Inflammatory or
Neuropathic Pain 9
2.1 Ion channels 9
2.2 Sodium channels 10
2.3 Calcium channels 12
2.4 K+ channels 12
2.5 Receptors 13
2.6 Purinergic receptors 13
2.7 Toll-like receptors 13
2.8 PAR receptors 14
2.9 Glutamate receptors 14
2.10 AMPA receptors 15
2.11 NMDA receptors 15
2.12 Metabotropic glutamate receptors 15
2.13 Opioid receptors 16
2.14 TRPV receptors 16
2.15 Prostaglandin (prostanoid) E2 17
2.16 Pronociceptive neurotransmitters 17
3. Summary 18
Acknowledgments 18
References 18
Abstract
The purpose of this chapter is to provide a brief introduction to the anatomy and phys-
iology of pain pathways from peripheral nociceptors to central nervous system areas
involved in the perception and modulation of pain. This chapter also provides a short
introduction to major types of persistent pain: neuropathic and inflammatory persistent
pain, and gives an overview of some important molecular targets that are thought to
mediate these types of pain. These targets, which include ion channels, receptors, and
Progress in Molecular Biology and Translational Science, Volume 131 # 2015 Elsevier Inc. 1
ISSN 1877-1173 All rights reserved.
http://dx.doi.org/10.1016/bs.pmbts.2015.01.003
2 Vaskar Das
some neurotransmitters, are further discussed in the context of their relevance as poten-
tial drug targets for the better treatment of pain in patients with persistent pain. Finally,
this chapter introduces several important concepts in pain research that will be primary
topics for chapters that come later in the book.
1. AN INTRODUCTION TO PAIN AND PAIN PATHWAYS

The International Association for the Study of Pain (IASP) has defined
pain as “an unpleasant sensory and emotional experience associated with
actual or potential tissue damage, or described in terms of such damage.”1
When asked to describe their pain, individuals variously described it in terms
of severity (mild, moderate, severe), duration (acute or chronic), and type
(nociceptive, inflammatory, neuropathic).2
Nociceptive pain is the normal acute pain sensation produced by activa-
tion of nociceptors in skin, viscera, and other internal organs in the absence
of sensitization.3–7 It may occur as a result of mechanical, thermal, or chem-
ical noxious stimulation and is variously described as an aching or throbbing
kind of pain.5,6,8,9 Nociceptive pain comprises four main stages: transduc-
tion (i.e., action at receptors in the periphery), transmission (i.e., action
potentials along axons), perception (i.e., cortical processing of nociceptive
input), and modulation (i.e., engagement of descending circuits).4,10–12
Noxious stimuli are first detected by mechanical, thermal, and chemical
nociceptors found on specialized nerve endings present in skin (cutaneous),
viscera, and other internal or external organs.8,9,13,14 Nociceptive impulses
are transmitted from the periphery to the spinal cord via primary afferent
nerve fibers which may be unmyelinated or myelinated.3,15–20 The central
nervous system (CNS) components of this pathway constitute particular
anatomical connections in the spinal cord, brain stem, thalamus, and cortex
(the “pain pathway”), linking the sensory inflow generated in high threshold
primary afferents with those parts of the CNS responsible for conscious
awareness of painful sensations21 (Fig. 1). Unmyelinated nerve fibers are
small diameter C-fibers with diameters in the range 0.4–1.2 μm.22,23
Myelinated primary afferent nerve fibers are the Að-fibers (2–6 μm diame-
ter), whereas the thinly myelinated nerve fibers are the Aβ-fibers (>10 μm
diameter).23,24 Primary afferent C-fibers and Að-fibers are responsible for
transmission of noxious stimuli whereas Aβ-fibers transmit innocuous,
mechanical stimuli such as touch.21–24 Put simply, nociceptors collect infor-
mation from noxious stimuli which are transmitted by C-fibers and
An Introduction to Pain Pathways and Pain “Targets” 3
Figure 1 Simplified schematic diagram of the pain pathway. Pain begins with detection
of damage or potentially damaging stimuli by nociceptive neurons in the periphery that
can transduce this signal into transmission toward the CNS. The first synapse in this
pathway is in the dorsal horn, where these projection neurons can send pain-related
information onto multiple brain areas. Pain perception occurs in the brain and can
be modulated by different centers in the brain. The brain also sends modulatory inputs
back down to the spinal cord to induce pain modulation.
Að-fibers through the dorsal root ganglia to the superficial laminae I/II of
the dorsal horn of the spinal cord.20,23 Að-fibers transmit impulses from
the dorsal horn to deeper laminae (III–IV) of the spinal cord and onto higher
centers in the brain via the spinothalamic tracts.20 Dorsal horn neurons com-
prise (i) projection neurons, (ii) local interneurons, and (iii) propriospinal
neurons.20,25 Although projection neurons are the primary means for trans-
ferring sensory information from the spinal cord to the brain, they are only a
small fraction of the total number of cells in the dorsal horn.23,26 Many
4 Vaskar Das
projection neurons have axons that cross the midline and ascend to multiple
areas of the brain including the thalamus, periaqueductal gray matter, lateral
parabrachial area of the pons, and various parts of the medullary reticular
formation.27 These neurons are also involved in activation of endogenous
descending inhibitory pathways that modulate dorsal horn neurons.26
Activity-dependent synaptic plasticity in the spinal cord that generates
postinjury pain hypersensitivity together with the cellular and molecular
mechanisms responsible for this form of neuronal plasticity are termed
“central sensitization.”21 Neuroplastic changes relating to the function,
chemical profile, or structure of the peripheral nervous system are
encompassed by the term “peripheral sensitization” and encompass changes
in receptor, ion-channel, and neurotransmitter expression levels.28,29
Central sensitization in the spinal cord includes sensitization and disinhibi-
tion mechanisms, and supraspinally there are functional changes such as
enlargement of receptive fields.30,31 In the CNS, there are also changes in
the dynamic interplay between neuronal structures and activated glial
cells,30,32,33 a topic covered in depth in Chapter “Nonneuronal Central
Mechanisms of Pain: Glia and Immune Response” by E. Alfonso
Romero-Sandoval and Sarah Sweitzer.
Following tissue injury and inflammation, vasoactive mediators such as
histamine, substance P (SP), serotonin (5-HT), nitric oxide (NO), prosta-
glandins (PGs), and bradykinin are released which activate nociceptors
resulting in nociception.13 This in turn can induce release of pronociceptive
neurotransmitters such as SP, calcitonin gene-related peptide (CGRP),
dynorphin (Dyn), neurokinin A (NKA), glutamate, adenosine triphosphate
(ATP), NO, PGs, and neurotrophins such as brain-derived neurotropic fac-
tor (BDNF), from primary afferents either in the periphery or at the first syn-
apse in the dorsal horn of the spinal cord.13,20,22,34,35 More recently, the
important role of proinflammatory cytokines (e.g., tumor necrosis factor-
alpha (TNF-α), interleukin-1β, interleukin-18, etc.) in peripheral and cen-
tral sensitization mechanisms associated with persistent pain states has begun
to be appreciated.36
Many C-fibers express transient receptor potential vanilloid 1 (TRPV1)
receptors and hence are sensitive to the vanilloid, capsaicin, which is a high-
affinity ligand for TRPV1 receptors.37 TRPV1-expressing C-fibers may be
further subdivided into two major classes:
(i) those that contain the neuropeptides, SP, and CGRP, express the high-
affinity nerve growth factor (NGF) receptor, TrkA, and are develop-
mentally dependent on NGF,34,38,39 and
(ii) those that express isolectin B4, (IB-4), the P2X3 purinergic receptor,40
fluoride-resistant acid phosphatase, do not contain SP or CGRP,41 and
are dependent on glial cell line-derived neurotrophic factor (GDNF).34
1.1 Neuropathic pain

The IASP has defined neuropathic pain as “Pain initiated or caused by a pri-
mary lesion or dysfunction in the nervous system.”1,42 Neuropathic pain is
variously described by patients as having one or more of the following qual-
ities: burning, tingling, electric shock like, and stabbing or pins and
needles.5,42,43 The appearance of abnormal sensory signs such as allodynia
in response to innocuous (nonnoxious) stimulation and/or hyperalgesia in
response to noxious stimulation is common.43 When neuropathic pain is
evoked, it may be classified as having dysesthetic, hyperalgesic, or allodynic
properties depending upon the dynamic or static characteristics of the
stimulus.44
In recent years, it has begun to be appreciated that the pathobiology of
various neuropathic pain subtypes may differ.45,46 Hence, multiple research
groups have focussed on developing and validating rodent models of each of
these neuropathic pain conditions.47,48 These more relevant rodent models
of neuropathic pain have considerable potential not only in terms of
unraveling the neurobiology of each of these neuropathic pain subtypes
but also in terms of identifying novel targets for discovery of new efficacious
and well-tolerated analgesics to improve relief of these persistent pain
conditions.43,49
Inflammatory and neuroimmune mechanisms contribute to both
peripheral and central sensitization that underpin the pathobiology of neu-
ropathic pain.50 Following peripheral nerve injury, inflammatory cells
including mast cells, neutrophils, macrophages, and T-lymphocytes contrib-
ute to peripheral sensitization and hyperexcitability of injured and adjacent
noninjured primary afferent nerve fibers.50 In the CNS, activation of glial
cells including microglia and astrocytes leads to the production and secretion
of various proinflammatory mediators that promote neuroimmune activa-
tion and can sensitize the central terminals of primary afferent and
second-order neurons to increase the intensity and duration of pain.50–53
However, rodent models of neuropathic pain allow behavioral pain
responses such as mechanical allodynia in response to application of a non-
noxious stimulus (light pressure) to the hindpaws and/or hyperalgesia in
response to application of noxious stimuli (pressure, heat, cold) to the
6 Vaskar Das
hindpaws, to be quantified.43,49 The three most commonly used rodent

models of neuropathic pain involve induction of a unilateral chronic con-
striction injury of the sciatic nerve,54 partial sciatic nerve ligation,55 and
L5 spinal nerve ligation.56 Over the past two decades, these models have
been used to identify numerous neuropathic pain “targets” encompassing
various receptors, ion channels, and enzymes, as well as to assess novel pain
therapeutics in development.43,49
More recently, rodent models of varicella zoster virus-induced neuro-
pathic pain, antiretroviral drug-induced neuropathic pain, cancer
chemotherapy-induced neuropathic pain, bone cancer pain, and multiple
sclerosis-induced neuropathic pain have been developed.43,57,58 It is hoped
that through use of these more sophisticated rodent pain models, it will be
possible to gain an enhanced understanding of the pathobiology of these
conditions. Additionally, it may be possible to identify novel “druggable”
targets for drug discovery aimed at producing novel analgesics with
improved efficacy and reduced adverse-event profiles for improved relief
of these chronic pain conditions in the clinical setting.49,59
Persistent ongoing pain secondary to nerve injury is underpinned by
considerable complexity and plasticity at multiple levels of the neu-
raxis.49,58,60–62 Following peripheral nerve injury, ectopic firing of injured
and uninjured afferents induces neuroplastic changes and “central
sensitization” in the spinal cord and the brain, underpinned by both neuro-
nal and nonneuronal mechanisms49 (Fig. 2). Intensive research over the past
two decades has revealed a large number of receptors, enzymes, and ion
channels as potential novel targets for drug discovery programs aimed at
Figure 2 Simplified diagram of mechanisms of neuropathic pain. Peripheral nerve

injury causes many changes in the function and phenotype of injured fibers, but an
important property for neuropathic pain is the generation of ectopic activity (action
potentials without any stimulus, signified by lightning). This ectopic activity drives spon-
taneous pain and plasticity in the dorsal horn and brain that may underlie clinical fea-
tures like allodynia.
producing new drugs for the relief of neuropathic pain.63–65 Although sev-
eral molecules have entered preclinical and clinical development, very few
have been approved by regulatory agencies for clinical use.66 Hence, this
large unmet medical need is driving research in this field.
1.2 Inflammatory Pain

Inflammatory pain is precipitated by an insult to the integrity of tissues at the
cellular level. One of the characteristic features of inflammatory states is that
normally innocuous stimuli can produce pain.67 Inflammation is classically
associated with pain (dolor), heat (calor), redness (rubor), swelling (tumor),
and loss-of-function (function laesa).67,68 Examples of inflammatory pain
include pain secondary to tissue injury and infection as well as rheumatoid
arthritis.69,70 Following tissue injury, nociceptors in the affected tissue become
sensitized due to the release of proinflammatory mediators from damaged cells
and blood vessels at the site of injury as well as from immune cells that invade
the injured site.71 This topic is covered in detail in Chapter “Peripheral
Scaffolding and Signaling Pathways in Inflammatory Pain by Jeske Nathan.”
Inflammatory mediators including protons, 5HT, histamine, adenosine,
bradykinin, prostaglandin E2 (PGE2), NO, IL-1, TNF-α, interleukin-6
(IL-6), leukemia inhibitory factor, and NGF5,72,73 contribute to nociceptor
sensitization so that innocuous stimuli are detected as painful (allodynia) or
there is an exaggerated response to noxious stimuli (hyperalgesia).34,74 The
central terminals of primary afferent nerve fibers (first-order neurons) are
located in the superficial layers (laminae I/II) of the dorsal horn of the spinal
cord.13 Synaptic input from these terminals to second-order neurons in the
spinal cord transfers information created by action potentials in primary
afferents secondary to peripheral noxious stimuli (depending on intensity
and duration), to the thalamus, and then onto the cerebral cortex in the
brain.13 Synaptic function at the central terminals of first-order neurons is
regulated by neurotransmitter release, primarily involving glutamate, and
neuroactive peptides like substance P and CGRP.60–62,75–78
In inflammatory pain, peripheral inflammation induces a phenotypic
switch in primary sensory neurons to induce a change in their neurochem-
ical character and properties.62 This topic is covered in some depth in Chap-
ters “Translation Control of Chronic Pain by Ohannes K. Melemedjian and
Arkady Khoutorsky,” “Regulation of Gene Expression and Pain States by
Epigenetic Mechanisms by S.M. Géranton and K.K. Tochiki,” and
“Commonalities between Pain and Memory Mechanisms and their Mean-
ing for Understanding Chronic Pain by Theodore J Price and Kufreobong E
Inyang.” In brief, this is underpinned by alterations in transcription and
8 Vaskar Das
translation of various receptors and ion channels to induce central sensitiza-

tion by virtue of a change in the level of synaptic input produced by the sen-
sitized afferent nerve fibers62 (Fig. 3). Put simply, continuous inputs from
sensitized nociceptive afferents can activate or trigger central sensitization
that is characterized by a reduced threshold of dorsal horn neurons to nox-
ious stimulation16,79–84 (Fig. 3). There is expansion of the receptive fields of
dorsal horn neurons,85,86 and temporal summation of slow postsynaptic
potentials resulting in a cumulative depolarization and a prolonged after dis-
charge or “wind up” of dorsal horn neurons.15 There is also increased excit-
ability of the flexion reflex in response to peripheral stimulation.82,87 The
neural mechanisms underlying central sensitization involve excitatory amino
acids (EAAs, e.g., mainly L-glutamate) acting at AMPA and NMDA recep-
tors with the net result being persistent activation of the NMDA receptor84
to allow Ca2+ entry into neurons and activation of numerous intracellular
signaling pathways.62
SP-expressing C-fibers and BDNF-expressing dorsal root ganglion
(DRG) neurons both have a significant role in inflammation-induced cen-
tral sensitization after exposure of their peripheral terminals to inflammatory
mediators and NGF released from immune cells.62,88,89 Ectopic firing of
sensitized terminals increase Aβ-mediated synaptic input to superficial dorsal
horn neurons62,90 and induction of cyclooxygenase-2 (COX-2) expression
levels to drive production of PGE2.62,91,92 Retrograde transport of NGF
from the peripheral terminals of C-fibers to the dorsal root ganglia induces
upregulation of TRPV1 expression and activation (phosphorylation) of p38
MAPK.39,93 This in turn leads to upregulated synthesis and release of
Figure 3 Simplified diagram of mechanisms of inflammatory pain. Activation of

immune cells during inflammation leads to the release of inflammatory mediators that
act on nociceptors. Many of these inflammatory mediators from immune cells directly
activate or modulate the activity of nociceptors. This can drive spontaneous pain and
plasticity in the dorsal horn and brain that underlies clinical features including allodynia
and hyperalgesia.
proinflammatory cytokines among which IL-1β and TNF-α contribute to

the development of central sensitization by enhancing excitatory and reduc-
ing inhibitory currents, and by activating induction of COX-2.62,91,94 As a
result, GluR2-containing AMPA receptor activation allows entry of Ca2+
into neurons,62,95 and this mechanism generates as much Ca2+ influx as
occurs with NMDA receptor activation during inflammatory pain.62,95
2. ION CHANNELS, RECEPTORS, AND OTHER “TARGETS”

FOR PERSISTENT INFLAMMATORY OR
NEUROPATHIC PAIN
Intensive research over the past two decades has revealed a vast array
of ion channels, receptors, transporters, and enzymes that are potential
“druggable” targets for use in discovery programs aimed at developing
the next generation of analgesic drugs.66 Examples of “pain targets” for
potential modulation by novel analgesic agents include voltage-gated
sodium channels (Nav1.3, Nav1.7, and Nav1.8),12 voltage-gated potassium
channels (Kv1.4) is the sole Kv1 subunit expressed in smaller diameter sen-
sory neurons96–98 suggesting that homomeric Kv1.4 channels predominate
in Aδ and C-fibers arising from these cells.97 By contrast, larger diameter
neurons associated with mechanoreception and proprioception express
high levels of Kv1.1 and Kv1.2 without Kv1.4 or other Kv1 subunits,
suggesting that heteromers of these subunits predominate on large, myelin-
ated afferent axons that extend from these cells.97,99–102 Additional “pain
targets” include voltage-gated calcium channels (VGCC) (α2δ subunits;
Cav2.2, Cav3.1, Cav3.2, Cav3.3),103 acid-sensing ion channels
(ASICs)104 covered to some extent in Chapter “Meningeal Afferent Signal-
ing and the Pathophysiology of Migraine by Carolina Burgos-Vega, Jamie
Moy and Greg Dussor,” NMDA receptors, TRPV1 receptors, covered in
Chapter “Sensory TRP Channels: The Key Transducers of Nociception
and Pain by Aaron D. Mickle, Andrew J. Shepherd and Durga P.
Mohapatra,” NKA, purinergic receptors, toll-like receptors (TLRs),
protease-activated receptors (PAR) receptors, opioid receptors, the norepi-
nephrine transporter, and cyclooxygenases (COX-1/2).105 Many of these
“pain targets” are described briefly in the following sections and in more
detail throughout this volume, as noted and summarized in Fig. 4.
2.1 Ion channels

Ion channels play a key role in nociception and are involved in sensory
transduction (TRPV1), regulation of neuronal excitability (potassium
10 Vaskar Das
Figure 4 Mechanisms of inflammation-induced pain in the periphery. Tissue damage

causes an immune response and the release of inflammatory mediators that act on
nociceptors. As described in the text, peripheral nociceptors are finely tuned to detect
mediators released by immune cells via the expression of receptors that bind these
ligands and the presence of ion channels that are altered by the signaling pathways
downstream of activation of these receptors.
channels), action potential propagation (sodium channels, ATP-gated chan-

nels, ASICs), and presynaptic release of various neurotransmitters (calcium
channels).106
2.2 Sodium channels

Voltage-gated sodium channels are considered a major target for the devel-
opment of novel therapies for improving pain management, as the ectopic
firing of primary afferents is associated with abnormal sodium channel
regulation.107–109
Sodium channels comprise an α-subunit containing a voltage-gated
sodium-selective aqueous pore and one or two smaller ancillary β-subunits.110
Sodium channel subtypes differ in their sensitivity to block by tetrodotoxin
(TTX) with six isoforms being sensitive (TTXs: Nav1.1, Nav1.2, Nav1.3,
Nav1.4, Nav1.6, Nav1.7) to block by nanomolar concentrations of TTX
and three isoforms being resistant to micromolar concentrations of TTX

(Nav1.5, Nav1.8, Nav1.9).111
Acute inflammatory and neuropathic pain can be attenuated or abolished
by local treatment with sodium channel blockers,112 showing that peripheral
nociceptive input is dependent on the presence of functional voltage-gated
sodium channels. Four voltage-gated sodium channel subtypes (Nav1.3,
Nav1.7, Nav1.8, and Nav1.9) are of greatest interest in pain due to their
selective expression in peripheral nerves.107,113–128 For first-order sensory
neurons, Nav1.8 is expressed by the cell body, peripheral terminals, and cen-
tral terminals within the dorsal horn of the spinal cord.110 Anatomical and
electrophysiological evidence indicates that expression of Nav1.9 is largely
restricted to nociceptive Aδ- and C-fibers.110
Highlighting the importance of Nav1.7 in inflammatory pain (Fig. 4),
levels of expression of Nav1.7 are increased in sensory nerve terminals by
inflammation12,128 and following ablation of Nav1.7 in nociceptive neurons,
inflammatory pain responses are greatly reduced.129 Additionally, dominant
gain-of-function mutations in SCN9A, the gene encoding Nav1.7 to
increase DRG neuron excitability are thought to be causal in two inherited
chronic pain disorders in humans, viz, erythromelalgia, characterized by
burning pain and skin redness in the extremities, and paroxysmal extreme
pain disorder, characterized by skin flushing, rectal, periocular, and peri-
mandibular pain evoked principally by mechanical stimuli.109,130 Addition-
ally, congenital indifference to pain due to rare recessive loss-of-function
mutations in SCN9A mean that although individuals so-affected are of nor-
mal intelligence, they often fail to recognize and report pain in response to
injury or infection which can lead to early mortality.131
Conditional knockout of SCN9A in mice abolished mechanical pain,
inflammatory pain, and reflex withdrawal responses to noxious heat recapit-
ulating the pain-free phenotype in humans with SCN9A loss-of-function
mutations.128 Interestingly, as conditional knockout of SCN9A in both sen-
sory and sympathetic neurons in mice with spinal nerve transection, mark-
edly reduced neuropathic pain behavior in these animals, neuropathic pain
therefore appears to involve interaction between sensory and sympathetic
neurons.128
In neuropathic pain, levels of expression of Nav1.3 are increased in dam-
aged peripheral nerves and this is highly correlated with the appearance of a
rapidly repriming sodium current in small DRG neurons consistent with the
notion that Nav1.3 channels make a key contribution to neuronal hyper-
excitability in neuropathic pain.12,105,110,132–135
12 Vaskar Das
2.3 Calcium channels

VGCCs play an important role in synaptic transmission and nociceptive
signaling.103,136–138 N-type (Cav2.2) VGCCs are expressed in high density
in the cell bodies of primary afferents in the dorsal root ganglia and on
presynaptic terminals that form synapses with second-order neurons in the dor-
sal horn.139–144 Cav2.2 channels regulate calcium entry, modulate neurotrans-
mitter release, and lead to changes in sensory nerve excitability for the
modulation of pain.67,145–147 Mice lacking Cav2.2 channels have reduced pain
responses secondary to inflammation and peripheral nerve injury.95,103,148,149
T-type VGCCs (Cav3.1, Cav3.2, and Cav3.3) are expressed on the cell
bodies and peripheral terminals of primary afferents, where they contribute
to initiation of the action potential to regulate neuronal excitability.103,150–152
Multiple studies in rodent pain models have implicated the α2δ1 subunit
of presynaptic calcium channels as having an important role in persistent pain
states.153 This is emphasized by clinical studies showing that the anti-
neuropathic drugs, gabapentin, and pregabalin that are ligands at the α2δ1
subunit, have efficacy for the relief of neuropathic pain.154–157 The mech-
anisms of action of these drugs are still controversial, but their widespread
use for neuropathic pain disorders is highlighted in Chapter “Chronic Pain
Syndromes, Mechanisms, and Current Treatments by Justin Sirianni,
Mohab Ibrahim and Amol Patwardhan.”
2.4 K+ channels
Voltage-gated K+ (Kv) channel subunits are expressed in DRG neurons and
have an important physiological role in the regulation of membrane poten-
tials in excitable tissues including nociceptive neurons.101,102,158–160 The Kv
channel subunit Kv1.4 is the sole Kv1 α subunit expressed in smaller diam-
eter neurons, suggesting that homomeric Kv1.4 channels predominate in Aδ
and C-fibers arising from these cells.97,99,100 Additionally, these neurons are
presumably nociceptors, because they also express the TRPV1 capsaicin
receptor, CGRP, and/or Na+ channel SNS/PN3/Nav1.8.97,99,161–164
However, larger diameter neurons associated with mechanoception and
proprioception express high levels of Kv1.1 and Kv1.2 without Kv1.4 or
other Kv1 α subunits, suggesting that heteromers of these subunits predom-
inate on large, myelinated afferent axons that extend from these
cells.97,99,100,164 As the opening of K+ channels leads to hyperpolarization
of the cell membrane and so decreased nerve cell excitability, several Kv
channels are implicated as possible targets for novel pain therapeutics. For
example, A-type potassium currents contribute significantly to neuronal

excitability and central sensitization in the dorsal horn of the spinal cord
in inflammatory pain.100,165–169
However, abnormal hyperexcitability of primary sensory neurons plays
an important role in neuropathic pain.164,166 Kv channels regulate neuronal
excitability by affecting the resting membrane potential and influencing the
repolarization and frequency of the action potential and may therefore play a
key role in ectopic activity that develops in peripheral nerves driving neu-
ropathic pain.163,164 Additionally, diabetes primarily reduces Kv channel
activity in medium and large DRG neurons.164 Increased BDNF activity
in these neurons likely contributes to the reduction in Kv channel function
through TrkB receptor stimulation in painful diabetic neuropathy.164
2.5 Receptors
In inflammatory pain, multiple receptor classes located on nociceptors are
modulated by vasoactive mediators released from damaged tissues and
immune cells that invade the inflamed tissues.170
2.6 Purinergic receptors

ATP activates P2X purinergic receptors, especially P2X1, P2X3, or P2X7
receptors, to produce pain.171–173 Currently, a range of preclinical studies
are investigating a role for P2X receptors in pain, inflammation, osteoporo-
sis, multiple sclerosis, spinal cord injury, and bladder dysfunction.173 Some
of these have been progressed into clinical trials for rheumatoid arthritis,
pain, and cough.173
P2X3 receptors, located exclusively on small diameter nociceptive-
fibers, are implicated in inflammatory pain and P2X4 receptors on microglia
in the dorsal horn of the spinal cord are implicated in the pathogenesis of
neuropathic pain.174 Antagonists at the P2X7 receptor also reduce pain
behaviors in rodent models of inflammatory and neuropathic pain, again
highlighting that purinergic glial–neuronal interactions are important mod-
ulators of noxious nociceptive neurotransmission.175 Hence, P2X3, P2X4,
and P2X7 receptors are potential targets for novel therapeutics for the treat-
ment of inflammatory and neuropathic pain conditions.176,177
2.7 Toll-like receptors

Proinflammatory central immune signaling contributes significantly to the
initiation and maintenance of heightened pain states because recent
14 Vaskar Das
discoveries have implicated the innate immune system, in particular, pattern

recognition TLRs in triggering these proinflammatory central immune sig-
naling events.178 There is considerable interest in the targeting of TLRs on
immune cells for the prevention and treatment of cancer, infection, inflam-
mation, and autoimmune diseases.179 In neuropathic pain, “TLR4 receptors
on peripheral immune cells (e.g., monocytes/macrophages, dendritic cells,
and immune-related cells such as keratinocytes)”170 as well as “activated
microglia in the CNS” appear to have a key role in the establishment of this
condition.180–183 Acute TLR4 antagonism attenuates neuropathic pain
behavior and potentiates opioid antinociception.184 Hence, TLR4 appears
to be a possible target for therapeutic intervention for relief of neuropathic
pain and for augmenting opioid analgesia. As already noted in an earlier sec-
tion of this literature review, dysregulation of chemokines (Section 1) and
their receptors (Section 2.1; Fig 4), particularly fractalkine and its CX3CR1
receptor, appear to play a key role in neuroimmune signaling that contributes
significantly to the pathobiology of neuropathic pain.185 This target is dis-
cussed in more detail in Chapter “Role of Extracellular Damage-Associated
Molecular Pattern Molecules (DAMPS) as Mediators of Persistent Pain by
Jungo Kato and Camilla I Svensson.”
2.8 PAR receptors

PARs are G-protein coupled receptors (GPCRs) that have a unique activa-
tion mechanism involving specific proteolytic cleavage of the amino-terminal
sequence by serine proteases.186–188 PAR1 is expressed by primary afferent
neurons and can modulate nociception.189 PAR2 is expressed by SP- and
CGRP-containing primary afferents.189 Activation of PAR2 induces the
release of the pronociceptive neurotransmitters, SP, and CGRP from both
peripheral and central terminals of primary DRG neurons.189 PAR4 modu-
lates nociceptive responses in normal and inflammatory conditions such that a
PAR4 agonist alleviated inflammatory pain in rats.159,188,190–196
2.9 Glutamate receptors

Glutamate is the major EAA neurotransmitter in the central nervous system
and is found in at least 70% of sensory neurons in the DRGs.197 It is released
from the central terminals of primary afferents and has an important role in
nociceptive neurotransmission.197 Glutamate acts via two main receptor
classes, iGluRs (ionotropic), and mGluRs (metabotropic) with iGluRs fur-
ther subdivided into AMPA, NMDA, and kainate receptors.72,198 AMPA
and NMDA receptors are directly coupled to cation-permeable ion channels

whereas metabotropic glutamate receptors (mGluRs) are coupled via
G-proteins to soluble second messengers.53,72,198–200 Brief nociceptive stim-
uli primarily activate AMPA receptors whereas stimuli of more prolonged
duration activate NMDA receptors.35,201 Astroglial cells remove excess glu-
tamate from the extracellular space and express the glutamate reuptake trans-
porters, GLAST/EEAT-1 (excitatory amino acid transporter) and glutamate
transporters EEAT-2/GLT-1.202–207
2.10 AMPA receptors

AMPA receptors have an important role in acute spinal processing of noci-
ceptive and nonnociceptive inputs.208 Activation of AMPA receptors by
glutamate results in potent depolarization of dorsal horn neurons to remove
the Mg2+ block, and hence activate NMDA receptors resulting in calcium
influx and initiation of a cascade of downstream signaling events.209 Because
AMPA receptors also have roles in many other CNS functions,208 they are
generally regarded as being unsuitable targets for development of novel pain
therapeutics.208
2.11 NMDA receptors

NMDA receptors (Fig. 1) are located in the superficial and deeper laminae of
the spinal dorsal horn on the central terminals of primary afferents as well as
on membranes that are postsynaptic to the primary afferent.210 All NMDA
receptors display a certain degree of voltage-dependent Mg2+ block and
marked permeability to Ca2+ after removal of the Mg2+ block
(Fig. 1).198,211–214 Spinal NMDA receptors have an important role in
“central sensitization” in the spinal cord in persistent pain states.215 Although
molecules targeting NMDA receptors have potential for the relief of persis-
tent pains such as neuropathic pain, NMDA receptors are involved in nor-
mal physiological functions and so the first generation of these agents were
hampered by CNS side effects in the analgesic dose range.216
2.12 Metabotropic glutamate receptors

Group I mGluRs in laminae I/II of the spinal dorsal horn play an important
role in the transduction of nociceptive input from C-fibers.217 There are
three mGluR classes containing eight cloned mGluRs and in vivo studies
show that these are not involved in acute nociceptive signaling.218–220
Group I mGluRs (mGlu1 and 5) are implicated in central sensitization
16 Vaskar Das
and persistent nociception.221 By contrast, activation of group II mGluRs

(mGlu2/3) alleviates neuropathic and inflammatory pain.221 This topic is
discussed in more detail in Chapter “mGluRs Head to Toe in Pain by
Benedict J. Kolber.”
2.13 Opioid receptors

Opioid receptors are members of the superfamily of 7-transmembrane span-
ning region GPCRs that are coupled to intracellular effectors via
G-proteins, mainly of the inhibitory type, i.e., Gi,o.25,222,223 There are high
densities of opioid receptors in various brain regions, the dorsal horn of the
spinal cord, on peripheral nerve terminals, in peripheral tissues including the
gastrointestinal tract and on immune cells (Fig. 2).198,224,225
In the 1990s, three opioid receptor types, viz, μ (MOP), δ (DOP), and κ
(KOP) were cloned, and more recently multiple splice variants of these
receptors, particularly the MOP receptor, have been identified.222,226–228
The endogenous ligands for opioid receptors include the endomorphins
(highly MOP selective), β-endorphin (equal MOP and DOP selectivity),
met- and leu-enkephalin (more selective at DOP than MOP), and Dyn
(KOP selective).229–231 Opioid agonists activate opioid receptors to produce
potent analgesia by activation of the descending inhibitory system to inhibit
ascending excitatory nociceptive transmission (Fig. 2).224,232,233 Studies
using MOP receptor knockout mice show that the antinociceptive and
other effects of morphine and most other clinically available opioid analge-
sics, are produced secondary to activation of the MOP recep-
tor.222,223,234–239 Studies using rodents show that peripheral opioid
actions are increased in inflammation, suggesting that peripherally selective
opioid analgesics may have benefit as future analgesic agents that are devoid
of CNS side effects.25,222
2.14 TRPV receptors

TRPV1 receptor (Fig. 4) is a ligand-gated nonselective cation channel
expressed on primary afferent sensory neurones that can be activated by
exogenous agents (e.g., capsaicin), endogenous substances (e.g., bradykinin,
ethanol, nicotine, anandamide, and insulin) as well as by heat (>43 °C) and
low pH.240–243 Following activation of TRPV1, there is a rapid increase in
intracellular Ca2+ concentrations resulting in nociceptive signal transduction
via C-fibers to produce pain in humans and pain behaviors in animals.243,244
TRPV1 knockout mice exhibit reduced thermal nociception and a loss of
inflammatory thermal hyperalgesia.242,245 However, both NGF and GDNF
elicit thermal hyperalgesia during peripheral inflammation via an increase in

TRPV1 expression.246 Expression of these two growth factors follows dif-
ferent time courses and they act on distinctive subpopulations of DRG neu-
rons.246 Intradermal injection of capsaicin and NGF produce heat
hyperalgesia via activation of their respective receptors, viz, TRPV1 and
TrkA on sensory nerve terminals. Moreover, PI3K induces heat
hyperalgesia, possibly by regulating TRPV1 activity, in an ERK-dependent
manner, and the PI3K pathway also appears to play a role that is distinct from
ERK (Fig. 4) by regulating the early onset of inflammatory pain.39,93,247,248
TRP channels are discussed in more detail in Chapter “Sensory TRP Chan-
nels: The Key Transducers of Nociception and Pain by Aaron D. Mickle,
Andrew J. Shepherd and Durga P. Mohapatra.”
2.15 Prostaglandin (prostanoid) E2

Inflammatory pain hypersensitivity is regulated by prostaglandin receptors
(EP1, EP2, EP3, EP4 receptors; Fig. 4).249 At the site of inflammation,
PGE2 sensitizes peripheral nociceptors via activation of EP2 receptors that
are present on the peripheral terminals of high threshold sensory nerve fibers
by reducing the nerve firing threshold and increasing responsiveness, which
is the key phenomenon of peripheral sensitization.249,250
Following tissue injury, the synthesis of PGE2 in the spinal cord91 con-
tributes to central sensitization251 and increased excitability of spinal dorsal
horn neurons.249 NSAIDs inhibit prostaglandin synthesis through non-
selective inhibition of constitutively expressed cyclooxygenase COX-1 as
well as the inducible isoform COX-2.252–254
2.16 Pronociceptive neurotransmitters

2.16.1 Nitric oxide
In the CNS, NO is synthesized primarily from the precursor, L-arginine, by
the enzyme nitric oxide synthase (NOS).255 There are three NOS isoforms,
viz, neuronal (nNOS), endothelial (eNOS), and inducible nitric oxide
synthase (iNOS), with nNOS having a role in the modulation of nociceptive
transmission in the spinal cord.255,256 Following glial cell activation in the
CNS, NO is produced by iNOS, to further sensitize nociceptive neurones
and contribute to the maintenance of central sensitization in persistent pain
conditions.256 NO produced in excess by iNOS and nNOS is implicated in
inflammatory and neuropathic pain, and so iNOS and nNOS inhibitors have
been investigated as potential novel agents for alleviation of these chronic
pain conditions.257
18 Vaskar Das
2.16.2 Nerve growth factor

NGF levels increase during inflammation258–260 resulting in sensitization of
primary afferents to noxious thermal, mechanical, and chemical stimuli via
upregulated synthesis of TRPV1 receptors as well as SP, CGRP, and bra-
dykinin receptors261–265 (Fig. 4). Anti-NGF therapeutics have advanced
to clinical trials in humans and have shown broad efficacy but also severe,
albeit rare, side effects. NGF signaling is discussed in more detail in Chapters
“Translation Control of Chronic Pain by Ohannes K. Melemedjian and
Arkady Khoutorsky” and “Commonalities between Pain and Memory
Mechanisms and their Meaning for Understanding Chronic Pain by
Theodore J Price and Kufreobong E Inyang.”
3. SUMMARY
Chronic pain is notoriously difficult to treat and so there is a large
unmet clinical need for new treatments to alleviate pain. Rodent models
of neuropathic and inflammatory pain have had a huge impact on our basic
understanding of pain and pain plasticity, a feature that will be discussed
throughout this volume. These basic science investigations have led to
the development of a broad variety of pain targets, some of which were dis-
cussed briefly here and some of which will be discussed in great detail
throughout the rest of this book. The goal of this line of research is to
develop a new generation of pain therapies with broad efficacy and limited
side effects.
ACKNOWLEDGMENTS
Dr. Das is grateful to Professors Maree Smith at University of Queensland and Theodore
Price at University of Texas at Dallas for editing of the chapter.
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An Introduction to Pain Pathways and Pain “Targets”

Article in Progress in Molecular Biology and Translational Science · March 2015

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An Introduction to Pain Pathways

1. AN INTRODUCTION TO PAIN AND PAIN PATHWAYS

1.1 Neuropathic pain

hindpaws, to be quantified.43,49 The three most commonly used rodent

Figure 2 Simplified diagram of mechanisms of neuropathic pain. Peripheral nerve

1.2 Inflammatory Pain

translation of various receptors and ion channels to induce central sensitiza-

Figure 3 Simplified diagram of mechanisms of inflammatory pain. Activation of

proinflammatory cytokines among which IL-1β and TNF-α contribute to

2. ION CHANNELS, RECEPTORS, AND OTHER “TARGETS”

2.1 Ion channels

Figure 4 Mechanisms of inflammation-induced pain in the periphery. Tissue damage

channels), action potential propagation (sodium channels, ATP-gated chan-

2.2 Sodium channels

and three isoforms being resistant to micromolar concentrations of TTX

2.3 Calcium channels

example, A-type potassium currents contribute significantly to neuronal

2.6 Purinergic receptors

2.7 Toll-like receptors

discoveries have implicated the innate immune system, in particular, pattern

2.8 PAR receptors

2.9 Glutamate receptors

and NMDA receptors are directly coupled to cation-permeable ion channels

2.10 AMPA receptors

2.11 NMDA receptors

2.12 Metabotropic glutamate receptors

and persistent nociception.221 By contrast, activation of group II mGluRs

2.13 Opioid receptors

2.14 TRPV receptors

elicit thermal hyperalgesia during peripheral inflammation via an increase in

2.15 Prostaglandin (prostanoid) E2

2.16 Pronociceptive neurotransmitters

2.16.2 Nerve growth factor

100. Takeda M, Tanimoto T, Nasu M, Matsumoto S. Temporomandibular joint inflamma-

143. Wermeling DP. Ziconotide, an intrathecally administered n-type calcium channel

186. Nguyen C, Coelho A-M, Grady E, et al. Colitis induced by proteinase-activated

251. Minami T, Nakano H, Kobayashi T, et al. Characterization of EP receptor subtypes

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